Eph-ephrin signaling couples endothelial cell sorting and arterial specification

Jonas Stewen, Kai Kruse, Anca T. Godoi-Filip, Zenia, Hyun-Woo Jeong, Susanne Adams, Frank Berkenfeld, Martin Stehling, Kristy Red-Horse, Ralf H. Adams () and Mara E. Pitulescu ()
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Jonas Stewen: Max Planck Institute for Molecular Biomedicine
Kai Kruse: Max Planck Institute for Molecular Biomedicine
Anca T. Godoi-Filip: Max Planck Institute for Molecular Biomedicine
Zenia: Max Planck Institute for Molecular Biomedicine
Hyun-Woo Jeong: Max Planck Institute for Molecular Biomedicine
Susanne Adams: Max Planck Institute for Molecular Biomedicine
Frank Berkenfeld: Max Planck Institute for Molecular Biomedicine
Martin Stehling: Max Planck Institute for Molecular Biomedicine
Kristy Red-Horse: Stanford University
Ralf H. Adams: Max Planck Institute for Molecular Biomedicine
Mara E. Pitulescu: Max Planck Institute for Molecular Biomedicine

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Cell segregation allows the compartmentalization of cells with similar fates during morphogenesis, which can be enhanced by cell fate plasticity in response to local molecular and biomechanical cues. Endothelial tip cells in the growing retina, which lead vessel sprouts, give rise to arterial endothelial cells and thereby mediate arterial growth. Here, we have combined cell type-specific and inducible mouse genetics, flow experiments in vitro, single-cell RNA sequencing and biochemistry to show that the balance between ephrin-B2 and its receptor EphB4 is critical for arterial specification, cell sorting and arteriovenous patterning. At the molecular level, elevated ephrin-B2 function after loss of EphB4 enhances signaling responses by the Notch pathway, VEGF and the transcription factor Dach1, which is influenced by endothelial shear stress. Our findings reveal how Eph-ephrin interactions integrate cell segregation and arteriovenous specification in the vasculature, which has potential relevance for human vascular malformations caused by EPHB4 mutations.

Date: 2024
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DOI: 10.1038/s41467-024-46300-0

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